Pain in the elderly people is often under-reported that leads to inadequate analgesia, slower recovery and poorer ambulation and function. The decreased pain sensitivity after aging is considered to be responsible for this but underlying mechanisms are not clear. A fundamental gap exists in our understanding whether structural, neurochemical, and molecular changes in the primary afferents lead to functional abnormalities, which contribute to the diminished pain sensitivity after aging. The long-term goal is to better understand mechanisms involved in the age-related diminished pain sensitivity. The objective of this application is to determine how age-related changes in the primary afferents affect normal pain sensitivity. The central hypothesis is that quantitative and functional changes in the afferents affect age- related altered nociception. The rationale for the proposed research is that, once it is known that aged subjects have defective function of afferents, the clinician will predict a greater level of underlying pathology when elderly people make a report of pain. Thus, the proposed research is relevant to that part of NIA s mission that pertains to promote research to develop new or improved approaches for disease and disability detection and diagnosis. Guided by our preliminary data in the young animals, our central hypothesis will be tested by pursuing the following three Specific Aims: 1) determine age-related changes in the density of primary afferent terminals in the epidermis;2) determine age-related changes in the conduction velocity of primary afferents and their ability to respond to mechanical, heat and cold stimuli;and 3) determine age- related changes in the pain threshold related behaviors. Under the first specific aim, we will use a double immunolabelling technique to quantify the density of epidermal afferent terminals in the glabrous part of part of hind paw skin. Under the second specific aim, we will use skin-nerve in vitro preparation to record the activity of single primary afferent axons innervating same tissues as used in specific aim 1. Under the third specific aim, heat pain, cold sensation, and tactile threshold related behaviors will be evaluated. In all three aims, results will be compared between four age groups. Previous studies that characterized primary afferent fibers in aged animals have utilized structural, biochemical, or molecular measures. The proposed research is innovative, because it would represent the first full-scale study to evaluate how functionality of afferent terminals is affected by aging (aim 2). The application takes advantage of single nerve fiber recording procedures in vitro, which to our knowledge is available in only a few laboratories in the USA. The successful completion of this project will have an important positive impact, because the identified functional anomalies of afferents are expected to provide knowledge about the effect of aging on functions of the pain pathway. It is expected that such an accomplishment will fundamentally advance our current level of understanding of the pain mechanisms related to aging. PUBLIC HEALTH RELEVANCE: The proposed studies are of an important and under-investigated area of aging research that has potential applicability to understanding functional abnormalities of pain receptors located in the skin surface and underlying causes for such abnormalities. The research has significance to public health, because it will identify why age-related decreases in pain sensitivity are observed in many clinical studies. Thus, the findings are ultimately expected to be applicable to develop a unique pain management strategy for elderly people.